美国安进科学研究公司Jude Canon和J. Russell Lipford研究团队发现，临床针对KRAS(G12C)的抑制剂AMG 510促进抗肿瘤免疫功能。 这一研究成果10月30日在线发表在国际学术期刊《自然》上。

研究人员使用可以显著增强结合相互作用效能和选择性的方法优化了一系列抑制剂。通过这种方法研究人员最终发现了AMG 510。据研究人员介绍，AMG 510是临床开发中第一种针对KRAS（G12C）的抑制剂。在临床前分析中，用AMG 510治疗导致KRAS^G12C肿瘤消退，并提高了化疗和靶向药物的抗肿瘤效果。在具有免疫能力的小鼠中，用AMG 510进行治疗可产生促炎性肿瘤微环境，AMG510与免疫检查点抑制剂联合使用可产生持久的治疗效果。治愈的小鼠抑制了等位基因KRAS^G12D肿瘤的生长，这提示对共享抗原的适应性免疫。此外，在临床试验中，AMG 510在首批给药组中显示出抗肿瘤活性，这对于缺乏有效治疗方法的患者而言，是一种潜在的转化疗法。

据悉，KRAS是癌症中最常见的突变致癌基因，在肿瘤细胞中编码关键的信号蛋白。 KRAS(G12C)突变体具有一个半胱氨酸残基，该残基已被用于设计具有良好临床前活性的共价抑制剂。

附：英文原文

Title: The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

Author: Jude Canon, Karen Rex, Anne Y. Saiki, Christopher Mohr, Keegan Cooke, Dhanashri Bagal, Kevin Gaida, Tyler Holt, Charles G. Knutson, Neelima Koppada, Brian A. Lanman, Jonathan Werner, Aaron S. Rapaport, Tisha San Miguel, Roberto Ortiz, Tao Osgood, Ji-Rong Sun, Xiaochun Zhu, John D. McCarter, Laurie P. Volak, Brett E. Houk, Marwan G. Fakih, Bert H. ONeil, Timothy J. Price, Gerald S. Falchook, Jayesh Desai, James Kuo, Ramaswamy Govindan, David S. Hong, Wenjun Ouyang, Haby Henary, Tara Arvedson, Victor J. Cee, J. Russell Lipford

Issue&Volume: 2019-10-30

Abstract: KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity35. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking. Treatment of KRASG12C-mutant cancer cells with the KRAS(G12C) inhibitor AMG 510 leads to durable response in mice, and anti-tumour activity in patients suggests that AMG 510 could be effective in patients for whom treatments are currently lacking.

DOI: 10.1038/s41586-019-1694-1

Source:https://www.nature.com/articles/s41586-019-1694-1